Hyperglycemia, glucose intolerance, and insulin "resistance" are frequent manifestations of the metabolic response to burn injury. In this project, we will attempt to define, via an integrated set of studies in burn patients, complemented by more invasive and mechanistically-based investigations in animal burn (rat, rabbit) models, the metabolic etiology for these changes in glucose homeostasis. Previous studies using the euglycemic, hyperinsulinemic damp technique have shown insulin resistance in peripheral tissues. However details of the mechanism of this resistance have not as yet been elucidated. We hypothesize that the principle organ sites responsible are skeletal muscle and liver and that the transmembrane transport of glucose and post- receptor events of insulin function are of casual significance. Therefore, the specific aims are: (1) Changes in the number and affinity of the insulin receptors and GLUT 4 transport proteins, as well as insulin pharmacokinetics may be important determinants of the rate of glucose transport, and so we will determine the effect of burn injury upon insulin receptor affinity and number; insulin pharmacokinetics in plasma; and the process of insulin internalization. (2) To assess defects in glucose transport and phosphorylation via dynamic imaging of 18F-2-deoxy-glucose uptake into skeletal muscle using PET, during basal and insulin-stimulated conditions. Studies will be performed in rabbits with 25% BSA burns, in healthy volunteers, and in patients with > 15% BSA burns at different times post-injury. Muscle will be obtained by biopsy during basal and insulin-stimulated conditions to measure GLUT 4 and the efficiency of translocation of insulin across the plasma membrane. (3) Finally, it is possible that the attenuation of phosphorylation of IRS-1 may play a major role in insulin resistance and so the expression of the insulin stimulated phosphorylated proteins in liver and muscle will be determined in burn injured animals. The phosphorylated proteins include IRS-1, Pl-3-kinase, IR, and P70, and the stress-induced phosphorylated proteins, SRPK kinase and p38. These studies will not only help to define the organ and cellular loci causally associated with burn-induced impairments in the glucose economy of the host but serve as a basis for the design of effective interventions.